Stress is a major factor in the onset and relapse to drug abuse. Over the past funding period, the effects of stress on the amygdala-locus coeruleus (LC) system, and how the response is altered after chronic stress exposure, was examined. In this resubmission, this will be extended to systems affected by the LC, and how they may impact drug abuse. Stress and drug abuse share a number of features in common, including the ability to release dopamine (DA) and norepinephrine (NE) in target structures, and a strong association with context. For this reason, this work focuses on one area in particular: the ventral subiculum (vSub) of the hippocampus. The vSub is centrally involved in context dependent processes, and increasing evidence points to its crucial role in regulating stress responsivity. Furthermore, we have shown that the vSub exerts potent control over DA neuron activity by controlling the population activity (i.e., proportion of DA neurons firing spontaneously), which sets the "gain" of the system when it responds to phasic events. Our preliminary data suggest that vSub-induced activation of DA neuron population activity may underlie behavioral sensitization to amphetamine. Thus, sensitization to amphetamine by stress or by repeated treatment leads to an increase in DA neuron population activity that can be circumvented by inactivation of the vSub. Moreover, both the amygdala and the NE system provide a strong activation of vSub neuron firing. Our central hypothesis is that both amphetamine treatment and stress exert a common action, i.e., vSub-mediated activation of DA neuron population activity, which underlies drug sensitization. We will pursue this using in vivo recordings in the vSub and from ventral tegmental DA neurons, using behavioral and microdialysis measures to confirm sensitized responses. We will explore this along the following specific aims: 1) Examine whether acute stressors or noxious stimuli activate the vSub, and whether this is dependent on NE and BLA afferents;this will show if stimuli known to lead to sensitization also activate the vSub. 2) Examine the effects of acute stressors on DA neuron activity and behavioral response to amphetamine, and if this is mediated via the vSub;this will evaluate the role of the vSub in stress-induced increase in DA neuron population activity. 3) Examine the effects of acute versus repeated amphetamine on DA neuron activity;this will evaluate whether increased DA neuron population firing as driven by the vSub also contributes to amphetamine-induced sensitization. 4) Examine how chronic stress alters DA neuron firing and amphetamine sensitization;this will extend our previous results on alterations in the amygdala-NE system during chronic stress, and how this impacts sensitization. The role of sensitization in drug taking is not clear;however, substantial data suggest that psychostimulant sensitization plays a central role in craving and relapse to drug-taking behavior. By gaining a better understanding of the neurobiological consequences of stress exposure, we hope to uncover the neuroadaptive changes that take place within the limbic system that predispose an individual to drug-taking behavior and contribute to relapse. Stress plays a major role in the propensity of humans to engage in drug-taking behavior and to suffer relapse, and is known to increase the rewarding properties of drugs such as amphetamine in animals. Both stress and amphetamine have common actions on the neurotransmitter dopamine in the brain. In this project, we test for common adaptive changes that are produced in a brain exposed to amphetamine and stress in order to better understand what causes people to become addicted and relapse to drug taking behavior, and to guide development of more effective long-term treatments for drug abuse.